Combined reduction in the expression of MCL-1 and BCL-2 reduces organismal size in mice

Abstract

The intrinsic apoptotic pathway is controlled by the BCL-2 family of proteins, which exhibit either a pro-death or prosurvival function. Gene knockout studies revealed that different pro-survival BCL-2 proteins are critical for the survival of distinct cell types, although overlapping functions amongst such proteins have also been identified. In the process of studying mice lacking single alleles of Mcl-1 (Mcl-1 +/−), Bcl-2 (Bcl-2 +/−), or both in combination (Mcl-1 +/− Bcl-2 +/−), we observed that Mcl-1 +/− Bcl-2 +/− mice weighed less when compared with their wild-type littermates as they aged. Body composition analysis demonstrated that while fat mass was similar to wild-type controls, lean mass was significantly reduced in Mcl-1 +/− , Bcl-2 +/− , and, most strikingly in Mcl-1 +/− Bcl-2 +/− mice. The weights of several tissues including the heart, tibialis anterior, and kidney were likewise reduced in Mcl-1 +/− Bcl-2 +/− mice. When lean mass and specific tissue weights were expressed relative to body weight, these differences were no longer significant, indicating that that Mcl-1 +/− Bcl-2 +/− mice, and to a lesser extent Mcl-1 +/− and Bcl-2 +/− mice, are smaller than their wild-type counterparts. Consistently, the anal-naso length was reduced in Mcl-1 +/− Bcl-2 +/− mice. While minor reductions in size were observed in female Mcl-1 +/− Bcl-2 +/− mice, these effects were most prominent in males. Notably, Mcl-1 +/− Bcl-2 +/− males had markedly smaller testes even after accounting for differences in body weight. Collectively, these data reveal that combined loss of a single allele of Mcl-1 and Bcl-2, while not overtly impairing organismal development, leads to a reduction in animal size.

Female‐to‐male differential transcription patterns of miRNA‐mRNA networks in the livers of dioxin‐exposed mice

“…In addition, kidneys from Brd4 ‐mutated mice had increased apoptosis 127 . Defects in Bcl2 , regulating cell death signaling, have been reported to correlate with autoimmunity and reduced organismal size in mice 128–130 . As pointed out, the expression of SOX9 was minimized in TCDD‐exposed male and this possibly affects testes development, a well characterized reproductive effect of TCDD on male mice 131,132 .…”

“…127 Defects in Bcl2, regulating cell death signaling, have been reported to correlate with autoimmunity and reduced organismal size in mice. [128][129][130] As pointed out, the expression of SOX9 was minimized in TCDD-exposed male and this possibly affects testes development, a well characterized reproductive effect of TCDD on male mice. 131,132 In addition, the dysregulation of SOX9 is apparently implicated in various congenital and acquired diseases, including fibrosis and cancer.…”

Apoptotic cell death in disease—Current understanding of the NCCD 2023

“…There are substantial differences in the severity of the defects caused by the conditional deletion of different pro-survival BCL2 family genes and between distinct tissues. For instance, conditional deletion of Mcl1 in mouse hematopoietic stem/progenitor cells [ 1214 ], erythroid cells [ 1258 ] or T REG cells [ 1259 ] is lethal. In the latter case, lethality is ascribed to multiorgan autoimmunity caused by the depletion of the pool of T REG cells [ 1259 ].…”

“…Moreover, the loss of one Bcl2l1 (encoding BCL-X L ) allele limits male fertility due to defects in germ cell development [1210] and shortens platelet lifespan [1211]. Of note, while combined haploinsufficiency for Mcl1 and Bcl2, for Mcl1 and Bcl2a1a or for Bcl2l1 (encoding BIM) and Bcl2 does not markedly affect embryonic development in mice [1212][1213][1214], Mcl1 +/− Bcl2l1 +/− double heterozygote mice display severe developmental defects and die during embryogenesis or early postnatally [1213]. Remarkably, this defect can be rescued by concomitant deletion of a single allele of the gene encoding BIM.…”

Targeting the BCL-2-regulated apoptotic pathway for the treatment of solid cancers

“…These pro-survival proteins are also essential for megakaryocyte survival [ 89 ]. Likewise, the loss of a single allele each of BCL2 and MCL1 in mice leads to reduced organismal size due to a reduction in body cellularity [ 90 ]. Nevertheless, co-targeting BCL-2 (with Venetoclax) and MCL-1 (with S64315 or AMG176) is in dose-finding clinical studies for the treatment of haematological malignancies (NCT03672695, NCT03797261) [ 91 ].…”